Acute kidney injury (AKI) resulting from ischemia-reperfusion injury represents a common problem in clinical nephrology and is associated with high mortality in the critical care setting. Furthermore, AKI is increasingly recognized as an important contributor to the progression of chronic kidney disease (CKD). A central pathway that allows renal cells to adapt to acute and chronic hypoxia is the pVHL/PHD/HIF pathway. Our laboratory and other groups have demonstrated that short-term HIF activation has great therapeutic potential for the prevention of acute ischemic injuries and their long-term sequelae. Prolonged epithelial HIF activation on the other hand results in renal inflammation and fibrosis. To understand the molecular and cellular basis of cytoprotection, we have begun to use genetic and pharmacologic approaches to dissect cell type-specific HIF functions and their role in the regulation of renal metabolism. Here we hypothesize that HIF-induced re- programming of renal metabolism plays a central role in determining the biological outcome of hypoxic kidney injuries. Under this grant we use genetically engineered mice and in vitro models of AKI to investigate the metabolic consequences of acute and chronic HIF activation in the kidney. Four specific aims are proposed. Aim 1 investigates the role epithelial PHD/HIF in ischemic AKI, aim 2 examines the metabolic changes that associate with acute and chronic HIF activation, aim 3 investigates the role of metabolic re-programming in the development of renal inflammation and fibrosis, and aim 4 investigates the molecular regulation of novel HIF targets that control metabolism. PUBLIC HEALTH RELEVANCE: This grant investigates the role of the VHL/HIF/PHD pathway in metabolic re- programming of the kidney. A major focus of this proposal is on acute ischemic kidney injury and the acute and chronic effects of HIF activation. Work proposed under this grant will further our understanding of molecular mechanism that leads to cytoprotection with the potential for therapeutic exploitation to improve the outcome of patients with ischemic kidney injuries.